Sphingosine Pathway Modulating Compounds For The Treatment Of Coronavirus Infection

ABSTRACT

The invention provides methods and compositions for treating a coronavirus infection using sphingosine kinase-1 inhibitors, such as SK1-I, and selective sphingosine-1-phosphate receptor agonists, such as ozanimod.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application Ser.No. 62/990,638 filed Mar. 17, 2020, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to the field of pharmaceutical treatment of viralinfections.

BACKGROUND

Sphingosine-1-phosphate (S1P) was discovered to be a bioactive signalingmolecule over 20 years ago. Studies have since identified two relatedkinases, sphingosine kinase 1 and 2 (a/k/a sphingosine kinase “type I”and “type II” respectively, and SphK1 and SphK2 respectively), whichcatalyze the phosphorylation of sphingosine to S1P. Extracellular S1Pcan bind to and activate each of five S1P-specific, G protein-coupledreceptors (designated S1PR₁₋₅) to regulate cellular and physiologicalprocesses in an autocrine or paracrine manner. Selective inhibitors ofeach of sphingosine kinase 1 and 2, as well as both non-selective andselective agonists of S1PRs, have been developed and are known in theart.

SUMMARY

One embodiment of the invention provides a method for treatingcoronavirus infection in a mammalian subject, such as a human, thatincludes the step of:

administering to a mammalian subject in need of treatment for acoronavirus infection, such as severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection, a therapeutically effective amountof a sphingosine kinase type I inhibitor or a pharmaceuticallyacceptable salt thereof, such as a sphingosine kinase type I inhibitordisclosed in U.S. Pat. Nos. 8,372,888 and/or 8,314,151, such as SK1-I,or a pharmaceutically acceptable salt thereof, for example ahydrochloride salt thereof.

A related embodiment of the invention provides a pharmaceuticalcomposition that includes a sphingosine kinase type I inhibitor or apharmaceutically acceptable salt thereof, such as SK1-I or apharmaceutically acceptable salt thereof, for the treatment ofcoronavirus infection, such as severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2), in a mammal, such as a human patient.

Another embodiment of the invention provides a method for treating acoronavirus infection in a mammalian subject, such as a human, thatincludes the step of:

administering to a mammalian subject in need of treatment for acoronavirus infection, such as severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection, a therapeutically effective amountof a sphingosine-1-phosphate receptor agonist, such as an agonist of oneor both of sphingosine-1-phosphate receptor-1 (S1P₁) andsphingosine-1-phosphate receptor-5 (S1P₅) such as ozanimod (RPC1063) ora pharmaceutically acceptable salt thereof, or an active metabolite ofozanimod or a pharmaceutically acceptable salt thereof.

Additional features, advantages, and embodiments of the invention may beset forth or apparent from consideration of the following detaileddescription, drawings if any, and claims. Moreover, it is to beunderstood that both the foregoing summary of the invention and thefollowing detailed description are exemplary and intended to providefurther explanation without limiting the scope of the invention asclaimed.

DETAILED DESCRIPTION

The invention provides new uses of sphingosine kinase-1 inhibitors, suchas SK1-I, and selective sphingosine-1-phosphate receptor agonists, suchas ozanimod, for treating coronavirus infections in mammalian subjects,such as human patients.

Sphingosine kinase 1 inhibitors used in various embodiments of theinvention may, for example, include any of those disclosed in U.S. Pat.Nos. 8,372,888 and/or 8,314,151, each of which is hereby incorporated byreference in its entirety herein, or pharmaceutically acceptable saltsthereof. The sphingosine kinase I inhibitor may, for example, be(E,2R,3S)-2-(methylamino)-5-(4-pentylphenyl)pent-4-ene-1,3-diol (alsoknown as SK1-I), or a pharmaceutically acceptable salt thereof such asbut not limited to a hydrochloride salt. The structure of SK1-I is shownbelow.

-   See also Paugh et al., Blood, 2008 112: 1382-1391.

The sphingosine kinase I inhibitor may, for example, be a compoundhaving the structure

or a pharmaceutically acceptable salt of the compound such as but notlimited to a hydrochloride salt.

The sphingosine kinase I inhibitor may, for example, be a compoundhaving the structure

wherein R is selected from a straight carbon chain, a branched carbonchain, a straight carbon chain comprising one or more heteroatoms, abranched carbon chain comprising one or more heteroatoms, a cyclic ring,a heterocyclic ring, an aromatic ring, a hetero-aromatic ring, or anycombination of the foregoing,

or a pharmaceutically acceptable salt thereof such as but not limited toa hydrochloride salt.

The sphingosine kinase I inhibitor may, for example, be a compoundhaving the structure

wherein R is 3,4-dimethoxy, 4-phenyl or 3-pentyl,

or a pharmaceutically acceptable salt thereof such as but not limited toa hydrochloride salt.

Sphingosine-1-phosphate receptor agonists used in various embodiments ofthe invention may, for example, be any of those disclosed in any of U.S.Pub. Nos. 20110172202, 20130231326, and 20150299149, or pharmaceuticallyacceptable salts thereof. The agonists may be agonists of one or both ofsphingosine-1-phosphate receptor-1 (S1P₁) and sphingosine-1-phosphatereceptor-5 (S1P₅) and may have little or at least no substantial agonistactivity against other sphingosine-1-phosphate receptors (in a mammalsuch as a human). The sphingosine-1-phosphate receptor agonist used may,for example, be5-[3-[(1S)-1-(2-hydroxyethylamino)-2,3-dihydro-1H-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-propan-2-yloxybenzonitrile(also known as ozanimod and RPC1063) or a pharmaceutically acceptablesalt thereof such as but not limited to a hydrochloride salt. Thestructure of ozanimod is shown below.

-   See also Scott et al., British Journal of Pharmacology 2016    173:1778-1792.

The sphingosine-1-phosphate receptor agonist may, for example, beetrasimod or a pharmaceutically acceptable salt thereof such as but notlimited to a hydrochloride salt. The structure of etrasimod is shownbelow.

The sphingosine-1-phosphate receptor agonist may, for example, beamiselimod or a pharmaceutically acceptable salt thereof such as but notlimited to a hydrochloride salt. The structure of amiselimod is shownbelow.

Without limitation, the following embodiments are also provided.

Embodiment 1. A method for treating coronavirus infection in a mammaliansubject, such as a human, including the step of:

administering to a mammalian subject in need of treatment for acoronavirus infection an effective amount of a sphingosine kinase type Iinhibitor.

Embodiment 2. The method of embodiment 1, wherein the coronavirusinfection is severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection.

Embodiment 3. The method of any one of the preceding embodiments,wherein the sphingosine kinase type I inhibitor at least substantiallydoes not inhibit sphingosine kinase type II.

Embodiment 4. The method of any one of the preceding embodiments,wherein the sphingosine kinase type I inhibitor includes a sphingosinekinase type I inhibitor disclosed in U.S. Pat. Nos. 8,372,888 and/or8,314,151, or a pharmaceutically acceptable salt thereof.

Embodiment 5. The method of any one of embodiments 1-4, wherein thesphingosine kinase type I inhibitor includes SK1-I or a pharmaceuticallyacceptable salt thereof.

Embodiment 6. The method of any one of the preceding embodiments,wherein said administration includes parenteral administration.

Embodiment 7. The method of embodiment 6, wherein said administration isvia injection, such as intravenous injection, intramuscular injection,or subcutaneous injection.

Embodiment 8. The method of any one of embodiments 1-5, wherein saidadministration includes non-parenteral administration.

Embodiment 9. The method of any one of embodiments 1-5, wherein saidadministration includes oral administration by ingestion.

Embodiment 10. The method of embodiment 9, wherein said oraladministration includes administering a dosage form including thesphingosine kinase type I inhibitor and at least one pharmaceuticallyacceptable excipient.

Embodiment 11. The method of embodiment 10, wherein the dosage form isselected from the group consisting of a tablet, a capsule, and a gelcap.

Embodiment 12. The method of any one of embodiments 1-5, wherein saidadministration includes administration via the alimentary canal.

Embodiment 13. The method of any one of the preceding embodiments,further including the step of:

co-administering to the subject an effective amount of ozanimod or apharmaceutically acceptable salt thereof.

Embodiment 14. A pharmaceutical composition for the treatment of acoronavirus infection in a mammalian subject, such as a human,including:

a therapeutically effective amount of a sphingosine kinase type Iinhibitor.

Embodiment 15. The pharmaceutical composition of embodiment 14, whereinthe coronavirus infection is severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection.

Embodiment 16. The pharmaceutical composition of any one of embodiments14 and 15, wherein the sphingosine kinase type I inhibitor at leastsubstantially does not inhibit sphingosine kinase type II.

Embodiment 17. The pharmaceutical composition of any one of embodiments14-16, wherein the sphingosine kinase type I inhibitor includes asphingosine kinase type I inhibitor disclosed in U.S. Pat. Nos.8,372,888 and/or 8,314,151, or a pharmaceutically acceptable saltthereof.

Embodiment 18. The pharmaceutical composition of any one of embodiment14-17, wherein the sphingosine kinase type I inhibitor includes SK1-I ora pharmaceutically acceptable salt thereof.

Embodiment 19. The pharmaceutical composition of any one of embodiments14-18, wherein said composition is for parenteral administration.

Embodiment 20. The pharmaceutical composition of embodiment 19, whereinsaid composition is for administration via injection, such asintravenous injection, intramuscular injection, or subcutaneousinjection.

Embodiment 21. The pharmaceutical composition of any one of embodiments14-18, wherein said composition is for non-parenteral administration.

Embodiment 22. The pharmaceutical composition of any one of embodiments14-18, wherein said composition is for oral administration by ingestion.

Embodiment 23. The pharmaceutical composition of any one of embodiment14-22, further including at least one pharmaceutically acceptableexcipient.

Embodiment 24. The pharmaceutical composition of any one of embodiments21 and 22, wherein said composition is a solid dosage form.

Embodiment 25. The pharmaceutical composition of embodiment 24, providedin a dosage form selected from the group consisting of a liquid, atablet, a capsule, and a gel cap.

Embodiment 26. The pharmaceutical composition of any one of embodiments14-18, wherein said composition is for administration via the alimentarycanal.

Embodiment 27. The pharmaceutical composition of any one of embodiments14-26, further including a therapeutically effective amount of ozanimodor a pharmaceutically acceptable salt thereof.

Embodiment 28. A method for treating a coronavirus infection in amammalian subject, such as a human, including the step of:

administering to a mammalian subject in need of treatment for thecoronavirus infection, such as a severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection, a therapeutically effective amountof a sphingosine-1-phosphate receptor agonist, such as an agonist of oneor both of sphingosine-1-phosphate receptor-1 (S1P₁) andsphingosine-1-phosphate receptor-5 (S1P₅) such as ozanimod (RPC1063) ora pharmaceutically acceptable salt (such as but not limited to ahydrochloride salt), ester, prodrug, homolog, hydrate or solvatethereof, or an active metabolite of ozanimod or a pharmaceuticallyacceptable salt (such as but not limited to a hydrochloride salt),ester, prodrug, homolog, hydrate or solvate thereof.

Embodiment 29. The method of embodiment 28, wherein thesphingosine-1-phosphate receptor agonist at least substantially does notagonize sphingosine-1-phosphate receptors other than types-1 and -5.

Embodiment 30. The method of any one of embodiments 28 and 29, whereinthe sphingosine-1-phosphate receptor agonist includes asphingosine-1-phosphate receptor agonist disclosed in any of U.S. Pub.Nos. 20110172202, 20130231326, and 20150299149 or a pharmaceuticallyacceptable salt (such as but not limited to a hydrochloride salt),ester, prodrug, homolog, hydrate or solvate thereof.

Embodiment 31. The method of any one of embodiments 28-30, wherein thesphingosine-1-phosphate receptor agonist includes ozanimod or apharmaceutically acceptable salt (such as but not limited to ahydrochloride salt), ester, prodrug, homolog, hydrate or solvatethereof.

Embodiment 32. The method of any one of embodiments 28-31, wherein saidadministration includes parenteral administration.

Embodiment 33. The method of embodiment 32, wherein said administrationis via injection, such as intravenous injection, intramuscularinjection, or subcutaneous injection.

Embodiment 34. The method of any one of embodiments 28-31, wherein saidadministration includes non-parenteral administration.

Embodiment 35. The method of any one of embodiments 34, wherein saidadministration includes oral administration by ingestion.

Embodiment 36. The method of embodiment 35, wherein said oraladministration includes administering a dosage form including thesphingosine-1-phosphate receptor agonist and at least onepharmaceutically acceptable excipient.

Embodiment 37. The method of embodiment 36, wherein the dosage form isselected from the group consisting of a liquid, a tablet, a capsule, anda gel cap.

Embodiment 38. The method of any one of embodiments 28-31, wherein saidadministration includes administration via the alimentary canal.

Embodiment 39. The method of any one of embodiments 28-38, furtherincluding the step of:

co-administering to the subject an effective amount of a sphingosinekinase type I inhibitor, such as SK1-I, or a pharmaceutically acceptablesalt thereof.

Embodiment 40. Use of a sphingosine kinase type I inhibitor as disclosedin U.S. Pat. Nos. 8,372,888 and/or 8,314,151, or a pharmaceuticallyacceptable salt thereof, such as but not limited to a hydrochloridesalt, such as SK1-I or a pharmaceutically acceptable salt thereof suchas but not limited to a hydrochloride salt, in the treatment ofcoronavirus infection, such as severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection, in a mammal such as a humanpatient.

Embodiment 41. Use of a sphingosine-1-phosphate receptor agonist, suchas an agonist of one or both of sphingosine-1-phosphate receptor-1(S1P₁) and sphingosine-1-phosphate receptor-5 (S1P₅) such as any ofthose disclosed in U.S. Pub Nos. 20110172202, and 20130231326, and20150299149, such as ozanimod (RPC1063), or a pharmaceuticallyacceptable salt (such as but not limited to a hydrochloride salt),ester, prodrug, homolog, hydrate or solvate thereof, or an activemetabolite of ozanimod or a pharmaceutically acceptable salt (such asbut not limited to a hydrochloride salt), ester, prodrug, homolog,hydrate or solvate thereof, for the treatment of coronavirus infectionin mammal, such as the treatment of severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection, in a mammal such as a humanpatient.

Embodiment 42. Any of the preceding embodiments that involve asphingosine-1-phosphate receptor agonist, wherein thesphingosine-1-phosphate receptor agonist is a compound having thestructure:

wherein,

X is —NR′R″ or —OR′″;

Y is —CN, —Cl, or —CF₃;

R′ is H, C₁₋₄ alkyl, n-hydroxy C₁₋₄ alkyl, —SO₂—R¹, or —CO—R¹;

R″ is H, —SO₂—R³, C₁₋₄ alkyl optionally substituted with 1 or more R²,or a ring moiety optionally substituted with R⁴ wherein such ring moietyis piperidinyl, cyclohexyl, morpholinyl, pyrrolidinyl, imidazolyl, orphenyl;

R′″ is H, C₁₋₄ alkyl, or —CO—R¹;

-   -   or alternatively, R′ and R″ taken together with the nitrogen        atom to which they are bound form a 4-, 5-, or 6-membered        saturated heterocyclic ring containing 0 or 1 additional        heteroatoms where such additional heteroatom is O or N wherein        such heterocycle is optionally singly or multiply substituted        with substituents independently selected from —OH, oxo, —NH₂,        n-hydroxy-C₁₋₄ alkyl, —COOH, —(CH₂)_(m)—COOH, —(CH₂)_(m)—COOR¹,        —N(R¹R¹), and —(CH₂)_(m)—CO—N(R⁵R⁵);

each R¹ is independently C₁₋₄ alkyl or H;

each R² is independently H, halo, OH, oxo, ═NH, NH₂, —COOH, F, —NHR¹,—N(R⁵R⁵), —SO₂—R¹, —SO₂—N(R⁵R⁵), —N(R¹)—SO₂—R¹, —COOR¹, —OCO—R¹,—CO—N(R⁵R⁵), —N(R¹)—COR¹, C₁₋₃ alkyl, C₁₋₃ alkoxy, and a ring moietyoptionally substituted with R⁴ wherein such ring moiety is piperazinyl,piperidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl,benzimidazolyl, azetidinyl, cyclobutinyl, or phenyl;

each R³ is independently R², C₁₋₄ alkyl, C₃₋₆ cycloalkyl, or C₁₋₄ alkyloptionally substituted with 1 or more R²;

each R⁴ is independently halo, OH, —NH₂, —NHR¹, —N(R¹R¹), —COOH, —COOR¹,—NHCO—R¹;

each R⁵ is independently C₁₋₄ alkyl or H, or alternatively two R⁵ takentogether with the nitrogen atom to which they are bound can form a 4-,5-, or 6-membered saturated heterocyclic ring containing 0 or 1additional heteroatoms where such additional heteroatom is O or Nwherein such heterocycle is optionally substituted with —OH, NH₂,—N(R¹R¹), n-hydroxy C₁₋₄ alkyl, —(CH₂)_(m)—COOH, or —(CH₂)_(m)—COOR¹;and

each m is independently 0, 1, 2, or 3, or a pharmaceutically acceptablesalt (such as but not limited to a hydrochloride salt), ester, prodrug,homolog, hydrate or solvate thereof.

Embodiment 43. Any of the preceding embodiments that involve asphingosine-1-phosphate receptor agonist, wherein thesphingosine-1-phosphate receptor agonist is a compound having thestructure:

or a pharmaceutically acceptable salt (such as but not limited to ahydrochloride salt), ester, prodrug, homolog, hydrate or solvatethereof. The compounds shown are active metabolites of ozanimod. X mayhave an (R) or (S) configuration where not specified.

Embodiment 44. Any of the preceding embodiments, wherein the mammal is ahuman patient in need of treatment for mild Coronavirus disease 2019,medium Coronavirus disease 2019, or severe Coronavirus disease 2019.

It should be understood that wherever this disclosure refers to thetreatment of a coronavirus infection generally or particularly, such astreatment of a severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection, treatment of the disease and disease conditionsassociated with or caused by the coronavirus infection is also beingdisclosed and is within the scope of treatment of the infection.Accordingly, wherever in this disclosure an embodiment for the treatmentof severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)infection is disclosed, an embodiment for treatment of the correspondingdisease, Coronavirus disease 2019 (COVID-19), is also being disclosed.

Administration may be as a single dose or as a divided dose. In oneembodiment, an effective dosage is administered once per month until thecondition is abated. In another embodiment, the effective dosage isadministered once per week, or twice per week or three times per weekuntil the condition is abated. An effective dosage may, for example, beadministered at least once daily or at least or at least once everytwo-days, or at least once every three days, four days, five days, sixdays or seven days. In another embodiment, an effective dosage amount isadministered about every 24 h until the condition is abated. In anotherembodiment, an effective dosage amount is administered about every 12 huntil the condition is abated. In another embodiment, an effectivedosage amount is administered about every 8 h until the condition isabated. In another embodiment, an effective dosage amount isadministered about every 6 h until the condition is abated. In anotherembodiment, an effective dosage amount is administered about every 4 huntil the condition is abated.

The therapeutically effective doses/amounts of the pharmaceuticalcompounds disclosed herein may be expressed in terms of the amount ofthe compound(s) or pharmaceutically acceptable salts thereofadministered per unit body weight of the subject per day of treatment,or the total amount administered per day of treatment. A daily dose may,for example, be at least 0.005 mg/kg of body weight, at least 0.01 mg/kgof body weight, at least 0.025 mg/kg of body weight, at least 0.05 mg/kgof body weight, at least 0.1 mg/kg of body weight, at least 0.2 mg/kg ofbody weight, at least 0.3 mg/kg of body weight, at least 0.4 mg/kg ofbody weight, at least 0.5 mg/kg of body weight, at least 0.6 mg/kg ofbody weight, at least 0.7 mg/kg of body weight, at least 0.8 mg/kg ofbody weight, at least 0.9 mg/kg of body weight, at least 1 mg/kg of bodyweight, at least 1.5 mg/kg of body weight, at least 2 mg/kg of bodyweight, at least 2.5 mg/kg of body weight, at least 3 mg/kg of bodyweight, at least 3.5 mg/kg of body weight, at least 4 mg/kg of bodyweight, at least 4.5 mg/kg of body weight, at least 5 mg/kg of bodyweight, or at one of said doses. A total daily dose may, for example, bein the range of 0.005 mg/kg to 5 mg/kg or any subrange or value therein,such as 0.025 to 5 mg/kg body weight, such as 0.05 to 5 mg/kg bodyweight. A total daily dose may, for example be in the range of 0.1 mg to1,000 mg total or any subrange or value therein, such as 0.1 mg to 1,000mg, such as 0.1 mg to 100 mg, such as 0.1 mg to 50 mg, such as 0.5 mg to50 mg, such as 1.0 mg to 50 mg, such as 5 mg to 50 mg, or 0.1 mg to 10mg, such as 0.5 mg to 10 mg.

For SK1-I and related SphK1 inhibitors disclosed U.S. Pat. Nos.8,372,888 and 8,314,151, and pharmaceutically acceptable salts thereof,a total daily dose for human subjects may, for example, also be in therange of 0.5 mg to 100 mg, such as 0.5 mg to 50 mg, such as 0.5 mg to 25mg, such as 0.5 mg to 20 mg. For SK1-I and related SphK1 inhibitorsdisclosed U.S. Pat. Nos. 8,372,888 and 8,314,151, and pharmaceuticallyacceptable salts thereof, a daily dose for human subjects may, forexample, also be in the range of 0.5 mg/kg to 5 mg/kg or any subrange orvalue therein, such as 1 mg/kg to 4 mg/kg, such as 1 mg/kg to 3 mg/kg,or, for example, a total daily dose of 5 mg to 50 mg or any subrange orvalue therein, such as 10 mg to 40 mg, such as 20 mg to 40 mg.

For ozanimod, its active metabolites and related sphingosine-1-phosphatereceptor agonists disclosed in U.S. Pub Nos. 20110172202, 20130231326,and 20150299149, and pharmaceutically acceptable salts thereof, a dailydose for human subjects may, for example, also be in the range of 1 mgto 50 mg or any subrange or value therein, or 0.1 mg to 10 mg or anysubrange or value therein, such as 0.1 mg to 5 mg, such as 0.5 to 5 mg,such as 0.5 mg to 2.5 mg, such as 0.5 mg to 1.5 mg. A pharmaceuticalcomposition according to the invention may, for example, include a dailydose amount of the compound as set forth herein.

The duration of treatment by administration of a therapeutic compound orcombination according to the invention may continue for a plurality ofdays, such as for at least one week, at least two weeks, at least threeweeks, at least four weeks, at least two months, at least three months,at least four months, at least five months, or generally until symptomssubside.

The terms co-administration and co-administering mean that each of thethings being co-administered is administered to a subject in suchtemporal proximity that each (or its active metabolite(s)) is present inactive form in the subject for an at least partially overlapping periodof time. Accordingly, co-administration may include, simultaneousadministration, such as when the things being administered are part ofthe same pharmaceutical composition, or sequential administration of thethings being co-administered, for example, within the same day of eachother, within 12 hours of each other, within 6 hours of each other,within 3 hours of each other, within 1 hours of each other, or within 15minutes of each other. The things being administered may be administeredby the same route, such as by oral ingestion or injection, or bydifferent routes.

Pharmaceutically acceptable salts and the selection and preparationthereof are well known in the art. Such salts include but are notlimited to hydrochloride, citrate, glycolate, fumarate, malate,tartrate, mesylate, esylate, cinnamate, isethionate, sulfate, phosphate,diphosphate, nitrate, hydrobromide, hydroiodide, succinate, formate,acetate, dichloroacetate, lactate, p-toluenesulfonate, pamitate,pidolate, pamoate, salicylate, 4-aminosalicylate, benzoate, 4-acetamidobenzoate, glutamate, aspartate, glycolate, adipate, alginate, ascorbate,besylate, camphorate, camphorsulfonate, camsylate, caprate, caproate,cyclamate, laurylsulfate, edisylate, gentisate, galactarate, gluceptate,gluconate, glucuronate, oxoglutarate, hippurate, lactobionate, malonate,maleate, mandalate, napsylate, napadisylate, oxalate, oleate, sebacate,stearate, succinate, thiocyanate, undecylenate, and xinafoate.

It should be noted that the indefinite articles “a” and “an” and thedefinite article “the” are used in the present application to mean oneor more unless the context clearly dictates otherwise. Further, the term“or” is used in the present application to mean the disjunctive “or” orthe conjunctive “and.” It should also be understood that wherever in thepresent application the term comprising or including (or a term ofsimilar scope) is recited in connection with the description of anyembodiment or part thereof, a corresponding embodiment or part thereofreciting instead the term consisting essentially of or the termconsisting of (or a term of similar scope) is also disclosed. It shouldalso be understood that wherever a chemical structure or chemical groupdisclosed herein has one or more stereoisomers or stereoisomeric forms,corresponding embodiments directed to each of the stereoisomers orstereoisomeric forms individually or to any combination of theparticular stereoisomers or stereoisomeric forms are also intended to bedisclosed.

All publications, patents, patent applications and other documents citedin this application are hereby incorporated by reference in theirentireties for all purposes.

While various specific embodiments have been illustrated and described,it will be appreciated that various changes can be made withoutdeparting from the spirit and scope of the invention(s). Moreover,features described in connection with one embodiment of the inventionmay be used in conjunction with other embodiments, even if notexplicitly exemplified in combination within.

What is claimed is:
 1. A method for treating coronavirus infection in amammal, comprising the step of: administering to a mammal in need oftreatment for coronavirus infection a therapeutically effective amountof ozanimod or a pharmaceutically acceptable salt thereof.
 2. The methodof claim 1, wherein the mammal is a human patient.
 3. The method ofclaim 1, wherein the administering step comprises administering thehydrochloride salt of the compound to the mammal.
 4. The method of claim3, wherein the mammal is a human patient.
 5. The method of claim 1,wherein the coronavirus infection is a severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection.
 6. The method of claim 2, whereinthe coronavirus infection is a severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection.
 7. The method of claim 6, whereinthe human patient has severe Coronavirus disease 2019 (COVID-19).
 8. Themethod of claim 3, wherein the coronavirus infection is a severe acuterespiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
 9. The methodof claim 4, wherein the coronavirus infection is a severe acuterespiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
 10. Themethod of claim 9, wherein the human patient has severe Coronavirusdisease 2019 (COVID-19).